Genomic imprinting, development and disease—is pre-eclampsia caused by a maternally imprinted gene?

1998 ◽  
Vol 10 (1) ◽  
pp. 23 ◽  
Author(s):  
Jennifer A. Marshall Graves
Keyword(s):  
Genomic Imprinting ◽  
Fetal Development ◽  
Mutant Gene ◽  
The Other ◽  
Paternal Allele ◽  
Imprinted Genes ◽  
Maternal Expression ◽  
Mutant Genes ◽  
Normal Placenta ◽  
Mode Of Inheritance

Several genes in conserved clusters are expressed from only the maternal or the paternal allele. The other allele has been genetically silenced (‘imprinted’) by its passage through one sex. Many known imprinted genes have effects on embryonic or trophoblast growth or fetal development, and mutation or loss of the single active copy causes diseases such as Prader–Willi, Angelmann and Beckwith–Wiederman syndromes. Imprinted genes show an unusual mode of inheritance, since mutant genes have an effect on the phenotype only if they come from the parent from which they are expressed. This may explain some conditions which appear to be heritable but show an inconsistant pattern in affected families. Of particular interest is pre-eclampsia/eclampsia, the most serious complication of pregnancy, which has some features suggesting that it results from fetal expression of the mutant gene, but others which imply it results from maternal expression. This could be resolved by proposing that the condition is due to mutation in a paternally imprinted, maternally active gene which must be expressed by the fetus in order to establish a normal placenta in the first pregnancy.

Imprinting analysis in the Acrodysplasia region of mouse chromosome 12

2009 ◽  
Vol 30 (2) ◽  
pp. 119-124 ◽  
Author(s):  
Erin N. McMurray ◽  
Eric D. Rogers ◽  
Jennifer V. Schmidt
Keyword(s):  
Mouse Chromosome ◽  
Genomic Imprinting ◽  
Critical Region ◽  
The Other ◽  
Chromosome 12 ◽  
Imprinted Genes ◽  
Skeletal Abnormalities ◽  
Mouse Mutation ◽  
Parent Of Origin

The insertional mouse mutation Adp (Acrodysplasia) confers a parent-of-origin developmental phenotype, with animals inheriting the mutation from their father showing skeletal abnormalities, whereas those inheriting the mutation from their mother are normal. This parental-specific phenotype, along with mapping of the insertion to a region of chromosome 12 proposed to contain imprinted genes, suggested that disruption of genomic imprinting might underlie the Adp phenotype. Genomic imprinting is the process by which autosomal genes are epigenetically silenced on one of the two parental alleles; imprinting mutation phenotypes manifest after inheritance from one parent but not the other. Imprinted genes typically occur in dense clusters that contain few non-imprinted genes and therefore representative genes from the Adp critical region could be assayed to identify any imprinted domains. None of the genes analysed were found to be imprinted, however, suggesting that other explanations for the Adp phenotype must be considered.

scholarly journals Multiple Imprinted Genes Associated with Prader-Willi Syndrome and Location of an Imprinting Control Element

1996 ◽  
Vol 45 (1-2) ◽  
pp. 87-89
Author(s):  
R.D. Nicholls ◽  
M.T.C. Jong ◽  
C.C. Glenn ◽  
J. Gabriel ◽  
P.K. Rogan ◽  
...  
Keyword(s):  
Genomic Imprinting ◽  
Epigenetic Modification ◽  
Uniparental Disomy ◽  
Paternal Allele ◽  
Control Element ◽  
Parental Origin ◽  
Imprinted Genes ◽  
Mammalian Development ◽  
Specific Expression ◽  
Large Deletions

Our studies aim to identify the mechanisms and genes involved in genomic imprinting in mammalian development and human disease. Imprinting refers to an epigenetic modification of DNA that results in parent-of-origin specific expression during embryogenesis and in the adult. This imprint is reset at each generation, depending on the sex of the parental gametogenesis. Prader-Willi (PWS) and Angelman (AS) syndromes are excellent models for the study of genomic imprinting in humans, since these distinct neurobehavioural disorders are both associated with genetic abnormalities (large deletions, uniparental disomy, and imprinting mutations) of inheritance in chromosome 15q11-q13, dependent on the parental origin (reviewed in ref. 1). Some AS patients have biparental inheritance, consistent with a single imprinted gene (active on the maternal chromosome), whereas similar PWS patients are not found suggesting that at least two imprinted genes (active on the paternal allele) may be necessary for classical PWS. We have previously shown that the small ribonucleoprotein associated protein SmN gene (SNRPN), located in the PWS critical region [2], is only expressed from the paternal allele and is differentially methylated on parental alleles [3]. Therefore, SNRPN may have a role in PWS. Methylation imprints have also been found at two other loci in 15q11-q13, PW71 [4] and D15S9 [5], which map 120 kb and 1.5 Mb proximal to SNRPN, respectively. We have now characterized in detail the gene structure and expression from two imprinted loci within 15q11-q13, SNRPN and D15S9, which suggests that both loci are surprisingly complex, with important implications for the pathogenesis of PWS.

scholarly journals Basics and disturbances of genomic imprinting

2020 ◽  
Vol 32 (4) ◽  
pp. 297-304
Author(s):  
Dirk Prawitt ◽  
Thomas Haaf
Keyword(s):  
Genomic Imprinting ◽  
Primordial Germ Cells ◽  
Uniparental Disomy ◽  
Point Mutations ◽  
Paternal Allele ◽  
Imprinted Genes ◽  
Specific Expression ◽  
Imprinting Disorders ◽  
Increased Risk ◽  
Genomic Imprints

Abstract Genomic imprinting ensures the parent-specific expression of either the maternal or the paternal allele, by different epigenetic processes (DNA methylation and histone modifications) that confer parent-specific marks (imprints) in the paternal and maternal germline, respectively. Most protein-coding imprinted genes are involved in embryonic growth, development, and behavior. They are usually organized in genomic domains that are regulated by differentially methylated regions (DMRs). Genomic imprints are erased in the primordial germ cells and then reset in a gene-specific manner according to the sex of the germline. The imprinted genes regulate and interact with other genes, consistent with the existence of an imprinted gene network. Defects of genomic imprinting result in syndromal imprinting disorders. To date a dozen congenital imprinting disorders are known. Usually, a given imprinting disorder can be caused by different types of defects, including point mutations, deletions/duplications, uniparental disomy, and epimutations. Causative trans-acting factors in imprinting disorders, including ZFP57 and the subcortical maternal complex (SCMC), have the potential to affect multiple DMRs across the genome, resulting in a multi-locus imprinting disturbance. There is evidence that mutations in components of the SCMC can confer an increased risk for imprinting disorders.

scholarly journals Genomic Imprinting

2021 ◽  
pp. 91-115
Author(s):  
Renato Paro ◽  
Ueli Grossniklaus ◽  
Raffaella Santoro ◽  
Anton Wutz
Keyword(s):  
Genomic Imprinting ◽  
The Other ◽  
Differentially Methylated Region ◽  
Evolutionary Constraints ◽  
Parental Origin ◽  
Seed Plants ◽  
Imprinted Genes ◽  
Expression Of Genes ◽  
Typical Cell ◽  
Two Kingdoms

AbstractA typical cell contains two sets of chromosomes: one that was inherited from the mother, the other from the father. Usually, autosomal alleles are expressed at similar levels from the maternally and paternally inherited chromosomes. This chapter is dedicated to an exception of this rule: the expression of genes that are regulated by genomic imprinting depends on the parental origin of the allele, leading to the non-equivalence of maternal and paternal genomes. Genomic imprinting is a paradigm of epigenetic gene regulation as genetically identical alleles can exist in two expression states within the same nucleus. The imprints marking the parental alleles are established in the parental germline, maintained during the development of the offspring, but reset before they are passed on to the next generation. In mammals, the primary imprint is usually a differentially methylated region at the locus but there are also examples where histone modifications mark the parental alleles. Many imprinted genes play important roles for development and are associated with human disease. Interestingly, genomic imprinting evolved independently in mammals and seed plants and similar mechanisms have been recruited to regulate imprinted expression in the two kingdoms. We will discuss evolutionary constraints that could have led to the evolution of genomic imprinting in these seemingly disparate lineages.

The Significance of Genomic Imprinting for Brain Development and Behaviour

2007 ◽  
Vol 19 (1-2) ◽  
pp. 133-134 ◽  
Author(s):  
Barry Keverne
Keyword(s):  
Genomic Imprinting ◽  
Germ Line ◽  
The Other ◽  
Maternal Behaviour ◽  
Imprinted Genes ◽  
Nutrient Metabolism ◽  
Genetic Transmission ◽  
Use Of Resources ◽  
Placental Blood ◽  
Pup Growth

Professor Barry Keverne FRS, FMedSci – Behavioural Neuroscience, King's College, Cambridge, described how genomic imprinting provides for co-adaptation of mother and fetus, for maternal provision and fetal use of resources. On the other hand it is open to genetic transmission of clinical disorders, for instance Prada-Willli syndrome leading to obesity, and Angelman's syndrome with mental retardation. Among vertebrates, genomic imprinting only evolved in mammals and the placenta is a primary target for expression of imprinted genes. There are certain autosomal genes in mammals that are only expressed if inherited from one parent rather than from the other. More often the paternal gene – allele – is expressed which means that the maternal allele is silenced, usually by methylation, bonding of a CH3 group. Genomic imprinting, distinct from epigenesis, occurs in germ-line cells, ensuring transgenerational effects. Epigenesis, in somatic cells, is usually restricted to one generation, although if it causes a change of behaviour – better mothering say – that can have consequences in the next generation by social transmission. Imprinting is reversible according to parent of origin and there is no change in the gene sequence, as occurs by mutation. Genomic imprinting acts primarily through key regulatory genes which in turn have a cascade effect through other genes. Possible effects vary widely, for instance the mother's food intake and weight gain; maternal fat and blood glucose; letdown of milk and post-natal pup growth. Other affects include her maternal behaviour, nest-building, and placental hormones, placental blood flow and nutrient transfer, fetal growth, and early weaning and puberty onset. In these ways the placenta enables the fetus to regulate its own destiny, mainly by genomic co-adaptation affecting hormonal action on receptors in the maternal hypothalamus. The two genomes, infant and maternal, are co-adaptive for infant wellbeing and reproductive success. Offspring that have extracted “good” maternal nurturing through imprinted genes will themselves be genetically predisposed towards good mothering. Through imprinting, a gene contributing to fitness is established in the population more quickly, especially when paternally expressed due to the greater reproductive fitness of males expressing this allele. Although genomic imprinting affects hormonal activity and nutrient metabolism, there is no evidence for hormones or nutrients affecting genomic imprinting. Hormones and nutrients can, particularly in early life, epigenetically affect the individual's future life for better or for worse, and significantly contribute to “foetal programming”.

scholarly journals Shared Role for Differentially Methylated Domains of Imprinted Genes

2002 ◽  
Vol 22 (7) ◽  
pp. 2089-2098 ◽  
Author(s):  
Bonnie Reinhart ◽  
Mariam Eljanne ◽  
J. Richard Chaillet
Keyword(s):  
Genomic Imprinting ◽  
Mutant Mouse ◽  
Paternal Allele ◽  
Mouse Strains ◽  
Imprinted Genes ◽  
Maternal Allele ◽  
Wild Type ◽  
Loss Of Imprinting ◽  
Intracisternal A Particle ◽  
Mouse Genomic

ABSTRACT For most imprinted genes, a difference in expression between the maternal and paternal alleles is associated with a corresponding difference in DNA methylation that is localized to a differentially methylated domain (DMD). Removal of a gene's DMD leads to a loss of imprinting. These observations suggest that DMDs have a determinative role in genomic imprinting. To examine this possibility, we introduced sequences from the DMDs of the imprinted Igf2r, H19, and Snrpn genes into a nonimprinted derivative of the normally imprinted RSVIgmyc transgene, created by excising its own DMD. Hybrid transgenes with sequences from the Igf2r DMD2 were consistently imprinted, with the maternal allele being more methylated than the paternal allele. Only the repeated sequences within DMD2 were required for imprinting these transgenes. Hybrid transgenes containing H19 and Snrpn DMD sequences and ones containing sequences from the long terminal repeat of a murine intracisternal A particle retrotransposon were not imprinted. The Igf2r hybrid transgenes are comprised entirely of mouse genomic DNA and behave as endogenous imprinted genes in inbred wild-type and mutant mouse strains. These types of hybrid transgenes can be used to elucidate the functions of DMD sequences in genomic imprinting.

scholarly journals Tissue-Specific Imprinting of the Mouse Insulin-Like Growth Factor II Receptor Gene Correlates with Differential Allele-Specific DNA Methylation

1998 ◽  
Vol 12 (2) ◽  
pp. 220-232 ◽  
Author(s):  
Ji-Fan Hu ◽  
Haritha Oruganti ◽  
Thanh H. Vu ◽  
Andrew R. Hoffman
Keyword(s):  
Dna Methylation ◽  
Growth Factor ◽  
Genomic Imprinting ◽  
Promoter Region ◽  
Receptor Gene ◽  
Paternal Allele ◽  
Imprinted Genes ◽  
Insulin Like Growth Factor ◽  
Peripheral Tissues ◽  
Factor Ii

Abstract Imprinted genes may be expressed uniparentally in a tissue- and development-specific manner. The insulin-like growth factor II receptor gene (Igf2r), one of the first imprinted genes to be identified, is an attractive candidate for studying the molecular mechanism of genomic imprinting because it is transcribed monoallelically in the mouse but biallelically in humans. To identify the factors that control genomic imprinting, we examined allelic expression of Igf2r at different ages in interspecific mice. We found that Igf2r is not always monoallelically expressed. Paternal imprinting of Igf2r is maintained in peripheral tissues, including liver, kidney, heart, spleen, intestine, bladder, skin, bone, and skeletal muscle. However, in central nervous system (CNS), Igf2r is expressed from both parental alleles. Southern analysis of the Igf2r promoter (region 1) revealed that, outside of the CNS where Igf2r is monoallelically expressed, the suppressed paternal allele is fully methylated while the expressed maternal allele is completely unmethylated. In CNS, however, both parental alleles are unmethylated in region 1. The importance of DNA methylation in the maintenance of the genomic imprint was also confirmed by the finding that Igf2r imprinting was relaxed by 5-azacytidine treatment. The correlation between genomic imprinting and allelic Igf2r methylation in CNS and other tissues thus suggests that the epigenetic modification in the promoter region may function as one of the major factors in maintaining the monoallelic expression of Igf2r.

scholarly journals In-utero stress and mode of conception: impact on regulation of imprinted genes, fetal development and future health

2019 ◽  
Vol 25 (6) ◽  
pp. 777-801 ◽  
Author(s):  
Maria Argyraki ◽  
Pauliina Damdimopoulou ◽  
Katerina Chatzimeletiou ◽  
Grigoris F Grimbizis ◽  
Basil C Tarlatzis ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Psychological Stress ◽  
Genomic Imprinting ◽  
Fetal Growth ◽  
Fetal Development ◽  
Environmental Chemicals ◽  
Imprinted Genes ◽  
Epigenetic Patterns

AbstractBACKGROUNDGenomic imprinting is an epigenetic gene regulatory mechanism; disruption of this process during early embryonic development can have major consequences on both fetal and placental development. The periconceptional period and intrauterine life are crucial for determining long-term susceptibility to diseases. Treatments and procedures in assisted reproductive technologies (ART) and adverse in-utero environments may modify the methylation levels of genomic imprinting regions, including insulin-like growth factor 2 (IGF2)/H19, mesoderm-specific transcript (MEST), and paternally expressed gene 10 (PEG10), affecting the development of the fetus. ART, maternal psychological stress, and gestational exposures to chemicals are common stressors suspected to alter global epigenetic patterns including imprinted genes.OBJECTIVE AND RATIONALEOur objective is to highlight the effect of conception mode and maternal psychological stress on fetal development. Specifically, we monitor fetal programming, regulation of imprinted genes, fetal growth, and long-term disease risk, using the imprinted genes IGF2/H19, MEST, and PEG10 as examples. The possible role of environmental chemicals in genomic imprinting is also discussed.SEARCH METHODSA PubMed search of articles published mostly from 2005 to 2019 was conducted using search terms IGF2/H19, MEST, PEG10, imprinted genes, DNA methylation, gene expression, and imprinting disorders (IDs). Studies focusing on maternal prenatal stress, psychological well-being, environmental chemicals, ART, and placental/fetal development were evaluated and included in this review.OUTCOMESIGF2/H19, MEST, and PEG10 imprinted genes have a broad developmental effect on fetal growth and birth weight variation. Their disruption is linked to pregnancy complications, metabolic disorders, cognitive impairment, and cancer. Adverse early environment has a major impact on the developing fetus, affecting mostly growth, the structure, and subsequent function of the hypothalamic–pituitary–adrenal axis and neurodevelopment. Extensive evidence suggests that the gestational environment has an impact on epigenetic patterns including imprinting, which can lead to adverse long-term outcomes in the offspring. Environmental stressors such as maternal prenatal psychological stress have been found to associate with altered DNA methylation patterns in placenta and to affect fetal development. Studies conducted during the past decades have suggested that ART pregnancies are at a higher risk for a number of complications such as birth defects and IDs. ART procedures involve multiple steps that are conducted during critical windows for imprinting establishment and maintenance, necessitating long-term evaluation of children conceived through ART. Exposure to environmental chemicals can affect placental imprinting and fetal growth both in humans and in experimental animals. Therefore, their role in imprinting should be better elucidated, considering the ubiquitous exposure to these chemicals.WIDER IMPLICATIONSDysregulation of imprinted genes is a plausible mechanism linking stressors such as maternal psychological stress, conception using ART, and chemical exposures with fetal growth. It is expected that a greater understanding of the role of imprinted genes and their regulation in fetal development will provide insights for clinical prevention and management of growth and IDs. In a broader context, evidence connecting impaired imprinted gene function to common diseases such as cancer is increasing. This implies early regulation of imprinting may enable control of long-term human health, reducing the burden of disease in the population in years to come.

scholarly journals Genomic imprinting in germ cells: imprints are under control

Reproduction ◽  
2010 ◽  
Vol 140 (3) ◽  
pp. 411-423 ◽  
Author(s):  
Philippe Arnaud
Keyword(s):  
Dna Methylation ◽  
Genomic Imprinting ◽  
Germ Cells ◽  
Imprinted Genes ◽  
Regulatory Sequences ◽  
Sequence Specificity ◽  
Maternal Allele ◽  
Primary Sequence ◽  
Chromatin Configuration

The cis-acting regulatory sequences of imprinted gene loci, called imprinting control regions (ICRs), acquire specific imprint marks in germ cells, including DNA methylation. These epigenetic imprints ensure that imprinted genes are expressed exclusively from either the paternal or the maternal allele in offspring. The last few years have witnessed a rapid increase in studies on how and when ICRs become marked by and subsequently maintain such epigenetic modifications. These novel findings are summarised in this review, which focuses on the germline acquisition of DNA methylation imprints and particularly on the combined role of primary sequence specificity, chromatin configuration, non-histone proteins and transcriptional events.

scholarly journals Genomic Imprinting of Dopa decarboxylase in Heart and Reciprocal Allelic Expression with Neighboring Grb10

2007 ◽  
Vol 28 (1) ◽  
pp. 386-396 ◽  
Author(s):  
Trevelyan R. Menheniott ◽  
Kathryn Woodfine ◽  
Reiner Schulz ◽  
Andrew J. Wood ◽  
David Monk ◽  
...  
Keyword(s):  
Genomic Imprinting ◽  
Promoter Region ◽  
Germ Line ◽  
Differential Methylation ◽  
Dopa Decarboxylase ◽  
Imprinted Genes ◽  
Chromosome 11 ◽  
Imprinted Gene ◽  
Line Methylation ◽  
Intron 1

ABSTRACT By combining a tissue-specific microarray screen with mouse uniparental duplications, we have identified a novel imprinted gene, Dopa decarboxylase (Ddc), on chromosome 11. Ddc_exon1a is a 2-kb transcript variant that initiates from an alternative first exon in intron 1 of the canonical Ddc transcript and is paternally expressed in trabecular cardiomyocytes of the embryonic and neonatal heart. Ddc displays tight conserved linkage with the maternally expressed and methylated Grb10 gene, suggesting that these reciprocally imprinted genes may be coordinately regulated. In Dnmt3L mutant embryos that lack maternal germ line methylation imprints, we show that Ddc is overexpressed and Grb10 is silenced. Their imprinting is therefore dependent on maternal germ line methylation, but the mechanism at Ddc does not appear to involve differential methylation of the Ddc_exon1a promoter region and may instead be provided by the oocyte mark at Grb10. Our analysis of Ddc redefines the imprinted Grb10 domain on mouse proximal chromosome 11 and identifies Ddc_exon1a as the first example of a heart-specific imprinted gene.

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